Clinical radiation therapy is a noninvasive means to mitigate cancer progression, which is prescribed for more than 50% of prostate cancer patients. Development of radiation technology, such as utilizing intensity- modulated radiotherapy (IMRT) to deliver highly conformal radiation dose distributions and image-guided radiotherapy (IGRT) to account for daily changes in target anatomy and positioning, allows unprecedented levels of accuracy and therapy outcome. The prostate is surrounded by many nerves and muscle fibers controlling different excretory and erectile functions that are difficult but necessary to avoid, it still remains a challenge to precisely deliver radiation doses to prostate cancer without damaging the normal surrounding tissues even with image guidance. To avoid excessive irradiation doses, radiosensitizers have been developed to amplify the effects of radiation within tumor cells. Prostate cancer targeted radiosensitizers may offer a means for further relative biological dose escalation with sparing of normal tissue. However, there has been limited preclinical and clinical investigation of targeted radiosensitizers for prostate cancer. To address the challenge, we aim to develop a nanoparticle technology that will improve prostate cancer tissue visualization and discrimination by MRI, allowing greater accuracy in MRI-guided radiation therapy, and provide radiosensitization within the cancer cells. Prostate specific membrane antigen (PSMA) is an ideal target to detect prostate cancer due to its abundant expression in most prostate cancers. We have synthesized a novel high-affinity ligand for PSMA targeting, and conjugated both targeting ligand and Gd(III) complex to gold nanoparticles and nanoclusters (AuNP/NCs). We have demonstrated that these PSMA-targeted AuNP/NC-Gd(III) have a much higher relaxivity than free Gd(III) agents and the NP/NCs can be selectively delivered to PSMA-expressing prostate tumor cells, providing MR image-guided radiation therapy. By delivering Gd(III) conjugated AuNP/NCs directly to prostate cancer cells we will 1) concentrate the Gd(III) agent to the nanoparticle surface while simultaneously calibrating the delivery of more Gd(III) agent to target tissues and less of the agent to non-specific or off-target sites; 2) improve r1 relaxivity and MR sensitivity, which potentially can reduce the given doses to patients and potentially toxicity of Gd(III) agents; 3) discriminate among cancerous, normal, neural, and muscle cells and tissues with MRI, enabling precise diagnosis of prostate cancer and precision radiation therapy; 4) combine gold and gadolinium together to enhance the radiosensitizing effect for potential ablation of prostate cancer using a lower radiation dose; and 5) enable MRI-guided radiotherapy using MRI LINAC device to enhance radiation accuracy and avoid collateral damage to normal tissues. We believe that this approach will impact the quality and success of radiotherapy. Further, PSMA is also expressed on the neovasculature of a number of different solid tumors, so this approach is proof-of-principal for radiation therapy and ablation for other cancers as well.
. In this proposal we will develop and optimize theranostic PSMA-targeted gold nanoparticle that act as a MR contrast agent as well as a radio-sensitizer. We will design, synthesize, characterize and optimize the utility of the particles in vitro and then utilize them for MR-guided radiotherapy in mice. These studies will lay the groundwork for this technology to be used for other cancers that express PSMA.
